Mono-- or diketone tetracyclic derivatives and therapeutical uses thereof

ABSTRACT

Invention concerning the therapeutic use of tetracyclic derivatives and their pharmaceutically acceptable salts having the following general formula: ##STR1## in which, independently of the other: X is a carbon or nitrogen atom, 
     T is a carbon or nitrogen atom, 
     L is an oxygen atom or ketone functional protective group, 
     R 1  is an atom of hydrogen, an atom of halogen, or a C 1  to C 5  alkyl radical, 
     R 2  is a hydrogen atom, a halogen atom, a nitro radical, or a C 1  to C 5  alkyl radical, 
     n and m are equal to 0 or to 1, but not independently of the other, so that if n is equal to 1, then m is equal to 0, and if n is equal to 0, then m is equal to 1.

This application is a 371 of PCT/FR96/01974 filed December 1996.

The present invention concerns the use of tetracyclic derivatives andtheir pharmaceutically acceptable salts for obtaining a medication forthe treatment of diseases involving an alteration in the venous functionand/or inflammatory edema, and concerns the new compounds obtained. Moreparticularly, it concerns derivatives of tetracyclic compoundscomprising a structural group, 1,4-dihydro-1,4-dioxonaphthalene, one ofthe ketones of which may be protected. The invention concerns thetherapeutic application of all these compounds.

The document, Chem. Rev., 63, 279-296 (1963) by M. F. Sartori describesthe synthesis of heterocyclic quinones from2,3-dichloro-1,4-dihydro-1,4-dioxonaphthalene, in particular,naphthoimidazopyridines, diones, and their derivatives.

The article, J. Amer. Chem. Soc. 79, 5708-5710 (1957) by P. Truitt, J.E. Cooper, and F. M. Wood, Jr. describes a controversial synthesis of6,11-dihydro-6,11-dioxonaphtho[2',3':4,5]imidazo[1,2-a] pyridine, whilethe document, J. Org. Chem., 24, 374-380 (1959), by W. L. Mosby and R.J. Boyle evokes the theoretical possibility of obtaining three types ofcompounds of different structures:5,6-dihydro-5,6-dioxo-naphtho[1',2':4,5]imidazo[1,2-a]pyridine,5,6-dihydro-5,6-dioxo-naphtho[1',2':4,5]-imidazo[2,3-a] pyridine,6,11-dihydro-6,11-dioxo-naphtho-[2',3':4,5]imidazo[1,2-a]pyridine. Theauthors demonstrate the obtaining of the first type of structure.Concerning this same problem, the article J. Org Chem., 26, 1316-1318(1961) by W. L. Mosby describes the possibility of obtaining two typesof products with similar reactions:5,6-dihydro-5,6-dioxo-naphtho[1',2':4,5]imidazo[1,2-a]pyridine (theso-called angular form) and6,11-dihydro-6,11-dioxo-naphtho[2',3':4,5]imidazo[1,2-a]pyridine (theso-called linear form). The authors note that the formation of thelinear structure is obtained less readily than the angular structure.More drastic conditions are thus required for the formation of thisstructure (reflux at elevated temperature). The "angular" structure ofthe family is demonstrated in the synthesis of5,6-dihydro-5,6-dioxo-naphtho[1',2':4,5]imidazo[1,2-a]pyridine using aspecific reagent of orthodiketones in the paper in J. Org. Chem., 28,1019-1022 (1963) by J. A. Van Allan and G. A. Reynolds.

U.S. Pat. No. 2,970,146, Jan. 31, 1961 (Cl. 260-256.4) by R. J. Boyle,O. G. Birsten, and W. L. Mosby describes the synthesis of newheterocyclic orthoquinones. The paper in Indian J. Chemistry 18B,236-239 (1979) by N. R. Ayyanger, A. G. Lugade, and B. D. Tilakdescribes the univocal synthesis of6,11-dihydro-6,11-dioxo-naphtho-[2',3':4,5]imidazo[1,2'-a]pyridine.

The paper in J. Indian Chem. Soc. 68(9), 529-531 (1991) by A. S Yannidescribes the synthesis and bactericidal and fungicidal activity of6,11-dihydro-6,11-dioxo -pyrido[1',2':1,2]imidazo[5,4-g]quinoline.Finally, German patent No. 1,108,699 by C. W. Schellhammer and G. Domagkdescribes the cytostatic and bacteriostatic activity of derivatives of5,6-dihydro-5,6-dioxo-pyrido[1',2':1,2]imidazo[4,5-f]quinoline.

The tetracyclic derivatives and their pharmaceutically acceptable saltsaccording to the present invention have the general formula: ##STR2## inwhich, independently of each other: X is a carbon atom or a nitrogenatom,

T is a carbon atom or a nitrogen atom,

R₁ is a hydrogen atom; a halogen atom, or an alkyl radical of C₁ to C₅,

R₂ is a hydrogen atom, a halogen atom, a nitro radical, of an alkylradical of C₁ to C₅,

n and m are equal either to 0 or 1, but not independently of each other,such that if n is equal to 1 then m is equal to 0 and if n is equal to 0then m is equal to 1.

The invention also concerns the following new products:

5,6-dihydro-5,6-dioxo-9-methyl-naphtho-[1',2':4,5]imidazo[1,2-a]pyridine;

5,6-dihydro-5,6-dioxo-10-methyl-naphtho-[1',2':4,5]imidazo[1,2-a]pyridine;

5,6-dihydro-5,6-dioxo-11-methyl-naphtho-[1',2':4,5]imidazo[1,2-a]pyridine;

11-chloro-5,6-dihydro-5,6-dioxo-naphtho-[1',2':4,5]imidazo[1,2-a]pyridine;

5,6-dihydro-5,6-dioxo-9-fluoro-naphtho-[1',2':4,5]imidazo[1,2-a]pyridine;

9-chloro-5,6-dihydro-5,6-dioxo-4-nitro-naphtho-[1',2':4,5]imidazo[1,2-a]pyridine;

6,11-dihydro-6,11-dioxo-2-methyl-naphtho-[2',3':4,5]imidazo[1,2-a]pyridine;

2-chloro-6,11-dihydro-6,11-dioxo-naphtho-[2',3':4,5]imidazo[1,2-a]pyridine;

4-chloro-6,11-dihydro-6,11-dioxo-naphtho-[2',3':4,5]imidazo[1,2-a]pyridine;

6,11-dihydro-6,11-dioxo-2-fluoro-naphtho-[2',3':4,5]imidazo[1,2-a]pyridine.

2-chloro-6,11-dihydro-6,11-dioxo-7-nitro-naphtho-[2',3':4,5]imidazo[1,2-a]pyridine

2-chloro-6,11-dihydro-6,11-dioxo-10-nitro-naphtho[2',3':4,5]imidazo[1,2-a]pyridine

10-chloro-5,6-dihydro-5,6-dioxonaphtho-[1',2':4,5]imidazo[1,2-a]pyridine

4-chloro-5,6-dihydro-5,6-dioxonaphtho-[1',2':4,5]imidazo[1,2-a]pyridine

4-bromo-5,6-dihydro-5,6-dioxonaphtho-[1',2':4,5]-imidazo[1,2-a]pyridine

5,6-dihydro-5,6-dioxo-2-nitronaphtho[1',2':4,5]-imidazo[1,2-a]pyridine

6,11-dihydro-6,11-dioxo-7-nitronaphtho-[2',3':4,5]imidazo[1,2-a]pyridine

6,11-dihydro-6,11-dioxo-10-nitronaphtho-[2',3':4,5]imidazo[1,2-a]pyridine

6,11-dihydro-6,11-dioxo-8-fluoronaphtho-[2',3':4,5]imidazo[1,2-a]pyridine

6,11-dihydro-6,11-dioxo-9-fluoronaphtho-[2',3':4,5]imidazo[1,2-a]pyridine

5,6-dihydro-5,6-dioxo-2-fluoronaphtho[1',2':4,5]-imidazo[1,2-a]pyridine

5,6-dihydro-5,6-dioxo-3-fluoronaphtho[1',2':4,5]-imidazo[1,2-a]pyridine

6,11-dihydro-6,11-dioxo-7-fluoronaphtho-[2',3':4,5]-imidazo[1,2-a]pyridine

6,11-dihydro-6,11-dioxo-10-fluoronaphtho-[2',3':4,5]imidazo[1,2-a]pyridine

5,6-dihydro-5,6-dioxo-1-fluoronaphtho[1',2':4,5]-imidazo[1,2-a]pyridine

5,6-dihydro-5,6-dioxo-4-fluoronaphtho[1',2':4,5]-imidazo[1,2-a]pyridine

4,9-dichloro-5,6-dihydro-5,6-dioxonaphtho-[1',2':4,5]imidazo[1,2-a]pyridine

6,11-dihydro-6,11-dioxo-7-fluoronaphtho-[2',3':4,5]imidazo[1,2-a]pyridine

6,11-dihydro-6,11-dioxo-10-fluoronaphtho-[2',3':4,5]imidazo[1,2-a]pyridine

5,6-dihydro-5,6-dioxo-1-methyl-naphtho[1',2':4,5]-imidazo[1,2-a]pyridine

5,6-dihydro-5,6--dioxo-4-methyl-naphtho[1',2':4,5]-imidazo[1,2-a]pyridine

9-chloro-6,11-dihydro-6,11-dioxo-7-methylnaphtho-[2',3':4,]imidazo[1,2-]pyridine

9-chloro-6,11-dihydro-6,11-dioxo-10-methyl-naphtho[2',3':4,]imidazo[1,2-a]pyridine

9-chloro-5,6-dihydro-5,6-dioxo-1-methylnaphtho-[1',2':4,]imidazo[1,2-a]pyridine

9-chloro-5,6-dihydro-5,6-dioxo-4-methylnaphtho-[1',2':4,5]imidazo[1,2-a]pyridine

6,11-dihydro-6,11-dioxo-8-methylnaphtho-[2',3':4,5]-imidazo[1,2-a]pyridine

6,11-dihydro-6,11-dioxo-9-methylnaphtho-[2',3':4,5]-imidazo[1,2-a]pyridine

5,6-dihydro-5,6-dioxo-2-methylnaphtho-[1',2':4,5]-imidazo[1,2-a]pyridine

5,6-dihydro-5,6-dioxo-3-methylnaphtho-[1',2':4,5]-imidazo[1,2-a]pyridine

The invention also concerns the following intermediate products:

2,3-dibromo-1,4-dihydro-1,4-dioxo-6-fluoro-naphthalene

2,3-dibromo-1,4-dihydro-1,4-dioxo-5-fluoro-naphthalene

2,3-dibromo-1,4-dihydro-1,4-dioxo-5-methyl-naphthalene

The invention also concerns the use of tetracyclic derivatives and theirpharmaceutically acceptable salts having the general formula (I) abovefor obtaining a specific medication:

for the treatment of functional and organic venous insufficiency;

for the treatment of hemorrhoidal pathologies;

for the treatment of migraine;

for the treatment of osteoarticular, dermatological and cardiovascularinflammations;

for the treatment of states of shock involving a substantial drop inarterial pressure, more particularly in states of septic shock.

Specifically, the compounds of the present invention have the generalformula (I) illustrated below: ##STR3## where: n=0 or 1; m=0 or 1; T=C,N; X=C, N; R₁ =H, CH₃, Cl, Br, F;

R₂ =H, NO₂, Cl, Br, F, CH₃

The present invention also concerns the salts of salifiable compounds offormula (I). These salts include the addition salts of inorganic acidssuch as hydrochloric, hydrobromic, sulfuric, phosphoric, or nitricacids, as well as the addition salts of organic acids such as acetic,propionic, oxalic, citric, maleic, fumaric, succinic, and tartaricacids.

The invention is illustrated by the following nonlimiting examples.

The examples indicated by a number correspond to new compounds, whilethe examples involving a letter correspond to known compounds.

In all the examples, the analyses are conducted as indicated below:

Melting points: They are obtained on an apparatus of the "Banc de Koflertype--LEICA--REICHERT, model WME.

Thin-layer chromatography: They were obtained on plates of silica gelwith fluorescence indicator UV₂₅₄, 0.25 mm in thickness, of theMACHEREY-NAGEL type (Reference 805 023). The elution solvents areindicated for each compound.

Mass spectra: They were produced either on a spectrometer of the AEIMS-50 type or on a spectrometer of the FISONS VG PLATFORM type. The modeof ionization is indicated for each analysis.

NMR spectra: The NMR spectra of ¹ H and ¹³ C were obtained either on aspectrometer of the JEOL type, respectively at 270 MHz and at 68 MHz, oron a spectrometer of the BRUCKER type, respectively at 400 MHz and at100 MHz. The deuterated solvents used are indicated for each analysis.

Infrared spectra: They were obtained on a spectrometer of the Nicolet205 FT-IR type. They were produced at 1% (m/m) in a dispersion in KBr.

EXAMPLE 1

5,6-Dihydro-5,6-dioxo-9-methyl-naphtho[1',2':4,5]-imidazo[1,2-a]pyridine

4.76 g (44 mmol) of 2-amino-5-methylpyridine in solution in 50 mL ofethanol are added to a suspension of 10 g (44 mmol) of2,3-dichloro-1,4-dihydro-1,4-dioxonaphthalene in 150 mL of ethanol,which is brought to reflux. After 48 h of reflux, the reaction mixtureis evaporated to dryness and purified on a flash column (support:silica; conditioning: heptane; eluent: dichloromethane) to produce 5 gof 5,6-dihydro-5,6-dioxo-9-methyl-naphtho[1',2':4,5]-imidazo[1,2-a]pyridine sulfate in the form of orange crystals.

Yield: 48%

Melting point: >260° C.

Rf: 0.54 (CH₂ Cl₂ /methanol, 98/2)

MS (I.E.): m/z 262 (M+.)

¹ H-NMR (CDCl₃): δ (ppm) 9.11 (s, 1H, H-8) 8.13 (m, 2H, H-1, H-4) 7.68(2m, 2H, H-2, H-3) 7.50 (m, 2H, H-10, H-11) 2.47 (s, 3H, CH₃)

¹³ C-NMR(CDCl₃): (ppm) 182.16, 167.14 (2C, Cquat) 153.85, 149.24 (2C,Cquat) 135.24, 134.95 (2C, C-2, C-3) 131.58 (1C, Cquat) 130.57 (2C,C-10, Cquat) 130.00, 124.48 (2C, C-1, C-4) 127.25 (1C, C-8) 120.40 (1C,Cquat) 117.39 (1C, C-11) 18.25 (1C, CH₃)

IR (KBr): μ (cm⁻¹) 1689, 1652 (C═O)

EXAMPLE 2

5,6-Dihydro-5,6-dioxo-10-methyl-naphtho[1',2':4,5]-imidazo[1,2-a]pyridine

2.16 g (20 mmol) of 2-amino-4-methylpyridine in solution in 50 mL ofethanol are added to a suspension of 4.54 g (20 mmol) of2,3-dichloro-1,4-dihydro-1,4-dioxonaphthalene in 200 mL of ethanol thatis brought to reflux. After 18 h of reflux, the reaction mixture isevaporated to dryness and purified on a flash column (support: silica;conditioning: heptane; eluent: dichloromethane) to produce 3.19 g of5,6-dihydro-5,6-dihydro-5,6-dioxo-10-methyl-naphtho[1',2':4,5]imidazo[1,2-a]pyridine.

Yield: 61%

Melting point: >260° C.

Rf: 0.64 (CH₂ Cl₂ /Methanol, 97/3)

MS (I.E.): m/z 262 (M+.)

¹ H-NMR (CDCl₃): (ppm) 9.11 (d, 1H, H-8, J_(H8-H9) =6.71 Hz) 8.08 (m,2H, H-1, H-4) 7.65, 7.53 (2m, 2H, H-2, H-3) 7.48 (m, 1H, H-11) 7.02 (d,1H, H-9, J_(H8-H9) =6.71 Hz) 2.52 (s, 3H, CH₃)

¹³ C-NMR (CDCl₃): (ppm) 182.39, 167.26 (2C, Cquat) 153.20, 150.79 (2C,Cquat) 144.48 (1C, Cquat) 135.22, 130.68 (2C, C-2, C-3) 131.51 (1C,Cquat) 130.02, 124.63 (3C, C-1, C-4, Cquat) 128.18 (1C, C-8) 120.01 (1C,Cquat) 118.99 (1C, C-11) 117.15 (1C, C-9) 22.00 (1C, CH₃)

IR (KBr): μ (cm⁻¹) 1701, 1656 (C═O)

EXAMPLE 3

5,6-Dihydro-5,6-dioxo-11-methyl-naphtho[1',2':4,5]-imidazo[1,2-a]pyridine

4.76 g (44 mmol) of 2-amino-3-methylpyridine in solution in 50 mL ofethanol are added to a suspension of 10 g (44 mmol) of2,3-dichloro-1,4-dihydro-1,4-dioxonaphthalene in 150 mL of ethanol thatis brought to reflux. After 48 h of reflux, the reaction mixture isevaporated to dryness and purified on a flash column (support: silica;conditioning: heptane; eluent: dichloromethane) to produce 6 g of5,6-dihydro-5,6-dioxo-11-methyl-naphtho[1',2':4,5]imidazo[1,2-a]pyridinein the form of orange crystals.

Yield: 52%

Melting point: >260° C.

Rf: 0.46 (CH₂ Cl₂ /Methanol, 99/1)

MS (I.E.): m/z 262 (M+.)

¹ H-NMR (CDCl₃): (ppm) 9.16 (d, 1H, H-8, J_(H8-H9) =6.72 Hz) 8.23 (d,1H, H-1, J_(H1-H2) =7.63 Hz) 8.11 (d, 1H, H-4, J_(H3-H4) =7.63 Hz) 7.69(dd, 1H, H-3, J_(H3-H4) =J_(H2-H3) =7.63 Hz) 7.50 (dd, 1H, H-2,J_(H2-H3) =J_(H1-H2) =7063 HZ) 7.43 (d, 1H, H-10, J_(H9-H10) =7.32 Hz)7.09 (dd, 1H, H-9, J_(H8-H9) =J_(H9-H10) =6.72 Hz) 2.72 (s, 3H, CH₃)

¹³ C-NMR (CDCl₃): (ppm) 182.29 (1C, C-5) 167.32 (1C, C-6a) 153.61 (1C,C-12a) 150.56 (1C, C-11a) 135.18 (1C, C-2) 131.73 (1C, C-4a) 131.32 (1C,C-10) 130.82 (1C, C-12b) 130.55 (1C, C-3) 130.00 (1C, C-4) 128.73 (1C,Cquat) 126.72 (1C, C-8) 124.75 (1C, C-1) 116.65 (1C, C-9) 16.87 (1C,CH₃)

IR (KBr): μ (cm⁻¹) 1691, 1646 (C═O)

EXAMPLE 4

11-Chloro-5,6-dihydro-5,6-dioxo-naphtho[1',2':4,5]-imidazo[1,2-a]pyridine

2.00 g (15.56 mmol) of 2-amino-3-chloropyridine are added to asuspension of 2.86 g (10.3 mmol) of 1,2-dihydro-1,2-dioxo-4-sulfonate ofpotassium naphthalene in 50 mL of distilled water. This mixture isbrought to reflux for 4 h and 30 min. After complete cooling, theprecipitate is filtered on fritted glass, washed with distilled water,and dried. The light brown solid obtained is purified on a flash column(support: silica; eluent: dichloromethane/ethyl acetate, 100/0 to 96/4)to produce 0.63 g of 11-chloro-5,6-dihydro-5,6-dioxo-naphtho[1',2':4,5]imidazo[1,2-a]pyridine.

Yield: 21%

Rf: 0.37 (CH₂ Cl₂ /ethyl acetate, 96/4)

MS (I.E.): m/z 282, 284 (M+.)

¹ H-NMR (CDCl₃): (ppm) 9.25 (d, 1H, H-8, J_(H8-H9) =6.71 Hz) 8.33 (d,1H, H-1, J_(H1-H2) =7.33 Hz) 8.15 (dd, 1H, H-4, J_(H3-H4) =7.94 Hz) 7.70(m, 2H, H-10, H-3) 7.54 (t, 1H, H-2, J_(H2-H3) =J_(H1-H2) 7.56 Hz) 7.14(t, 1H, H-9, J_(H8-H9) =J_(H9-H10) =6.91 Hz)

¹³ C-NMR (CDCl₃): (ppm) 135.50 (1C, C-2) 131.08 (1C, C-10) 130.95 (1C,C-3) 130.33 (1C, C-4) 127.40 (1C, C-8) 125.32 (1C, C-1) 124.61 (1C,C-11) 116.35 (1C, C-9)

IR (KBr): μ (cm⁻¹) 1653 (C═O)

EXAMPLE 5

5,6-Dihydro-5,6-dioxo-5-fluoro-naphtho[1',2':4,5]imidazo[1,2-a] pyridine

0.635 g (5.7 mmol) of 2-amino-5-fluoropyridine is added to a suspensionof 1.200 g (4.3 mmol) of 1,2-dihydro-1,2-dioxo-4-sulfonate of potassiumnaphthalene in 40 mL of water. The reaction mixture is heated to refluxfor 3 h. After complete cooling, the precipitate formed is filtered onfritted glass, washed with water and dried. The red solid obtained ispurified on a flash column (support: silica; eluent:dichloromethane/ethyl acetate, 100/0 to 90/10) to produce 0.023 g of5,6-dihydro-5,6-dioxo-9-fluoro-naphtho[1',2':4,5]imidazo[1,2-a]pyridinein the form of yellow crystals after decoloration with animal black.

Yield: 2%

Rf: 0.42 (CH₂ Cl₂ /ethyl acetate, 90/10)

MS (I.E.): m/z 266 (M+.)

¹ H-NMR (270 MHz, CDCl₃): d (ppm) 9.27 (m, 1H, H-8, J_(H8-F) =4.88 Hz)8.17, 8.15 (2d, 2H, H-1, H-4, J_(H1-H2) =J_(H3-H4) =7.32 Hz) 7.80 (dd,1H, H-10, J_(H10-H11) =9.77 Hz, J_(H10-F) =4.88 Hz) 7.71 (t, 1H, H-2,J_(H1-H2) =J_(H2-H3) =7.63 Hz 7.53 (m, 2H, H-3, H-11)

IR (KBr): μ (cm⁻¹) 1686, 1654, 1633 (C═O)

EXAMPLES 6 and 7

2-Chloro-6,11-dihydro-6,11-dioxo-7-nitronaphtho[2',3':4,5]imidazo[1,2-a]pyridine or2-Chloro-6,11-dihydro-6,11-dioxo-10-nitronaphtho[2',3':4,5]imidazo[1,2-a]pyridine and9-Chloro-5,6-dihydro-5,6-dioxo-4-nitronaphtho[1',2':4,5]imidazo[1,2-a]pyridine

2.50 g (19.0 mmol) of 2-amino-5-chloropyridine are added to a solutionof 2.50 g (11.0 mmol) of2,3-dichloro-1,4-dihydro-1,4-dioxo-5-nitronaphthalene in 500 mL ofethanol. This mixture is heated to reflux for 62 h and 50 min. Thesolution passes from yellow to claret-colored, then to orange. Aftercooling, the reaction mixture is filtered. The precipitate is washedwith ethanol, then dried in an oven for 20 h. The precipitate obtainedis recrystallized in 650 mL of ethanol. This precipitate is purified ona flash column (support: silica; eluent: dichloromethane). 0.260 g of2-chloro-6,11-dihydro-6,11-dioxo-7-nitronaphtho[2',3':4,5]imidazo[1,2-a]-pyridineor2-chloro-6,11-dihydro-6,11-dioxo-10-nitronaphtho[2',3':4,5]imidazo[1,2-a]pyridine is obtained in the form of orange crystals, and 0.495 g of10-chloro-5,6-dihydro-5,6-dioxo-4-nitronaphtho[1',2':4,5]imidazo[1,2-a]pyridine is formed in the form of orange crystals.

2-Chloro-6,11-dihydro-6,11-dioxo-7-nitronaphtho[2',3':4,5]imidazo[1,2-a]pyridine or2-Chloro-6,11-dihydro-6,11-dioxo-10-nitronaphtho[2',3':4,5]limidazo[1,2-a] [pyridine]

Yield: 9%

Melting point: >260° C.

Rf: 0.75 (CH₂ Cl₂ /MeOH, 93/2)

MS (I.E.): 327, 329 (M⁺.)

¹ H-NMR (CD₂ Cl₂): δ (ppm) 9.38 (dd, 1H, H-1, J_(H1-H3) =1.66 Hz,J_(H1-H4) =0.83 Hz) 8.30 (dd, 1H, H-10 or H-7, J_(H9-H10) or J_(H7-H8)=7.05 or 7.47 Hz, J_(H8-H10) or J_(H7-H9) =2.08 or 1.66 Hz) 7.82 (dd,1H, H-4, J_(H3-H4) =9.55 Hz or J_(H1-H4) =0.83 Hz) 7.60(m, 3H, H-3, H-8et H-9)

IR (KBr): ν (cm⁻¹) 1650 (C═O), 1540, 1400 (NO₂)

9-Chloro-5,6-dihydro-5,6-dioxo-4-nitronaphtho[1',2':4,5]imidazo[1,2-a]pyridine

Yield: 13%

Melting point: >260° C.

Rf: 0.35 (CH₂ Cl₂ /MeOH, 98/2)

MS (I.E.): 327, 329 (M⁺.)

¹ H-NMR (CD₂ Cl₂): δ (ppm) 9.30 (dd, 1H, H-8, J_(H8-H10) =2.16 Hz,J_(H8-H11) =0.83 Hz) 8.40 (dd, 1H, H-1, J_(H1-H2) =7.89 Hz, J_(H1-H3)=1.25 Hz) 7.86 (t, 1H, H-2, J_(H2-H3) J_(H1-H2) =7.89 Hz) 7.82 (dd, 1H,H-11, J_(H10-H11) =9.55 Hz, J_(H8-H11) =0.83 Hz) 7.68 (dd, 1H, H-10,J_(H10-H11) =9.55 Hz or J_(H8-H10) =2.16 Hz) 7.52 (dd, 1H, H-3,J_(H2-H3) =7.89 Hz or J_(H1-H3) =1.25 Hz)

¹³ C-NMR (CD₂ Cl₂): δ (ppm) 166.94 (1C, Cquat) 136.87 (1C, C-2) 134.26(1C, C-1) 127.58 (1C, C-3) 119.26 (1C, C-11)

IR (KBr): ν (cm⁻¹) 1650 (C═O), 1540(NO₂)

EXAMPLE 8

6,11-Dihydro-6,11-dioxo-2-methyl-naphtho[2',3':4,5]imidazo[1,2-a]pyridine

0.55 g (5.08 mmol) of 2-amino-5-methylpyridine is added to a suspensionof 0.45 g (2.16 mmol) of3-chloro-1,4-dihydro-1,4-dioxo-2-hydroxynaphthalene in 15 mL of1,2-dimethoxyethane. The reaction medium is brought to reflux for 21 h.After complete cooling, it is diluted with 120 mL of dichloromethane.The organic phase is washed successively with a saturated solution ofsodium hydrogen carbonate and sodium chloride, then dried on sodiumsulfate and evaporated under reduced pressure. The raw product obtainedis purified on a medium-pressure column (support: silica; eluent:dichloromethane/heptane/ethyl acetate, 68/40/2) to produce 0.096 g of6,11-dihydro-6,11-dioxo-2-methyl-naphtho[2',3':4,5]imidazo[1,2-a]pyridinein the form of yellow crystals after decoloration with animal black.

Yield: 17%

Rf: 0.34 (CH₂ Cl₂ /ethyl acetate, 94/6)

MS (I.E.): m/z 262 (M+.)

¹ H-NMR (CD₂ Cl₂): (ppm) 9.21 (s, 1H, H-1) 8.22 (m, 2H, H-7, H-10) 7.78(m, 3H, H-4, H-8, H-9) 7.49 (dd, 1H, H-3, J_(H3-H4) =9.16 Hz, J_(H1-H3)=1.52 Hz) 2.48 (s, 3H, CH₃)

IR (KBr): ν (cm⁻¹) 1685 (C═O)

EXAMPLE 9

2-Chloro-6,11-dihydro-6,11-dioxo-naphtho[2',3':4,5]imidazo[1,2-a]pyridine

1.58 g (12.30 mmol) of 2-amino-5-chloropyridine are added to asuspension of 1.29 g (6.21 mmol) of3-chloro-1,4-dihydro-1,4-dioxo-2-hydroxynaphthalene in solution in 10 mLof 1,2-dimethoxyethane. The reaction medium is brought to reflux for 23h. After complete cooling, the medium is diluted in 10 mL of water. Theprecipitate is filtered, washed with water and heptane, and dried. Theprecipitate is then diluted in dichloromethane and the organic phase iswashed successively with a saturated solution of sodium hydrogencarbonate and sodium chloride. The organic phase is dried on sodiumsulfate, filtered, and evaporated under reduced pressure. The rawproduct obtained is purified on a flash column (support: silica; eluent:dichoromethane/heptane/methanol, 79.5/20.0/0.5) to produce 0.07 g of2-chloro-6,11-dihydro-6,11-dioxo-naphtho[2',3':4,5]imidazo[1,2-a]pyridine in the form of yellow crystals after decoloration withanimal black.

Yield: 4%

Melting point: >300° C.

Rf: 0.27 (CH₂ Cl₂ /ethyl acetate, 96/4)

MS (I.E.): m/z 282 (M+.)

¹ H-NMR (CD₂ Cl₂): (ppm) 9.49 (d, 1H, H-1, J_(H1-H3) =2.13 Hz) 8.25 (m,2H, H-7, H-10) 7.87 (d, 1H, H-4, J_(H3-H4) =9.77 Hz) 7.79 (m, 2H, H-8,H-9) 7.61 (dd, 1H, H-3, J_(H3-H4) =9.76 Hz, J_(H1-H3) =2.13 Hz)

¹³ C-NMR (CD₂ Cl₂): (ppm) 183.08 (1C, C═O) 178.13 (1C, C═O) 162.73,160.86 (2C, Cquat) 149.26, 148.08, 146.75 (3C, Cquat) 134.59, 134.30(2C, C-8, C-9) 132.53 (1C, C-3) 130.40 (1C, C-2) 127.70, 126.85 (2C,C-7, C-10) 126.73 (1C, C-1) 120.24 (1C, C-4)

IR (KBr): ν (cm⁻¹) 1686, 1651 (C═O)

EXAMPLE 10

4-Chloro-6,11-dihydro-6,11-dioxo-naphtho[2',3':4,5]imidazor[1,2-a]pyridine

850 mg (2.66 mmol) of2-(3-chloro-2-pyridylamino)-3-chloro-1,4-dihydro-1,4-dioxonaphthalene insolution in 80 mL of glycerol is brought to 190° C. for 20 min. Aftercomplete cooling, the yellow precipitate obtained is filtered on frittedglass, washed w-th distilled water, and recrystallized in methanol afterdecoloration with animal black to produce 300 mg of4-chloro-6,11-dihydro-6,11-dioxo-naptho[2',3':4,5]imidazo[1,2-a]pyridinein the form of yellow crystals.

Yield: 40%

Melting point: >300° C.

Rf: 0.10 (CH₂ Cl₂)

MS (I.E.): m/z 282 (MH+.)

¹ H-NMR (CD₂ Cl₂): δ (ppm) 9.37 (dd, 1H, H-1, J_(H1-H2) =7.01 Hz,J_(H1-H3) =0.91 Hz) 8.26 (m, 2H, H-7, H-10) 7.81 (m, 2H, H-8, H-9) 7.71(dd, 1H, H-3, J_(H3-H2) =7.63 Hz, J_(H3-H1) =0.91 Hz) 7.21 (t, 1H, H-2,J_(H2-H3) =7.32 Hz)

IR (KBr): ν (cm⁻¹) 1682, 1649 (C═O)

EXAMPLE 11

6,11-Dihydro-6,11-dioxo-2-fluoro-naphtho[2',3':4,5]imidazo[1,2-a]pyridine

0.98 g (8.75 mmol) of 2-amino-5-fluoropyridine is added to a suspensionof 0.98 g (4.72 mmol) of3-chloro-1,4-dihydro-1,4-dioxo-2-hydroxynaphthalene in solution in 10 mLof 1,2-dimethoxyethane. The reaction medium is brought to reflux for 23h. After complete cooling, the medium is diluted in 10 mL of water. Theprecipitate is filtered, washed with water and heptane, and dried. Theprecipitate is diluted in dichloromethane, then the organic phase iswashed successively with a saturated solution of sodium hydrogencarbonate, then sodium chloride. The organic phase is dried on sodiumsulfate, filtered, then evaporated under reduced pressure. The rawproduct obtained is purified on a flash column (support: silica; eluent:dichloromethane/methanol, 99/1) to produce 0.03 g of6,11-dihydro-6,11-dioxo-2-fluoro-naphtho[2',3':4,5]-imidazo[1,2a]pyridine in the form of yellow crystals after decoloration with animalblack.

Yield: 2.3%

Rf: 0.55 (CH₂ Cl₂ /ethyl acetate, 96/4)

MS (I.E.): m/z 266 (M+.)

¹ H-NMR (CD₂ Cl₂): (ppm) 9.37 (m, 1H, H-1, J_(H1-F) =J_(H1-H3) =3.36 Hz)8.25 (m, 2H, H-7, H-10) 7.91 (dd, 1H, H-4, J_(H3-H4) =9.76 Hz, J_(H4-F)=4.88 Hz) 7.80 (m, 2H, H-8, H-9) 7.56 (m, 1H, H-3, J_(H3-H4) =10.07 Hz,J_(H3-F) =7.94 Hz, J_(H1-H3) =2.75 Hz)

IR (KBr): ν (cm⁻¹) 1686, 1681 (C═O)

EXAMPLE 12

10-Chloro-5,6-dihydro-5,6-dioxo-naphtho[1',2':4,5]-imidazo[1,2-a]pyridine

3.27 g (25.9 mmol) of 2-amino-4-chloropyridine are added to a suspensionof 6.64 g (28.9 mmol) of 2,3-dichloro-1,4-dihydro-1,4-dioxonaphthalenein 95 mL of glycerol. This mixture is heated to 205° C. for 10 min. Thesolution passes from yellow to dark brown.

After complete cooling, 5 mL of methanol are added to the reactionmedium, then it is extracted with dichloromethane. The organic phase isdried, filtered, and evaporated to dryness.

This precipitate is purified on a cake (support: silica; eluent:heptane/dichloromethane/ethyl acetate, 100/0/0 to 0/95/5). The solidobtained is recrystallized in chlorobenzene to produce 0.16 g of10-chloro-5,6-dihydro-5,6-dioxo-naphtho[1',2':4,5]imidazo-[1,2-a]pyridine in the form of orange crystals aftertreatment with animal black, then passage through a micropore filter.

Yield: 2%

Melting point: >300° C.

Rf: 0.30 (CH₂ Cl₂ /AcOEt, 96/4)

MS (I.E.): m/z 282/284 (M⁺.), 254/256 (M-CO)

¹ H-NMR (CD₂ Cl₂): δ (ppm) 9.28 (d, 1H, H-8, J_(H8-H9) =6.67 Hz) 8.28(d, 1H, H-1, J_(H1-H2) =6.13 Hz) 8.20 (d, 1H, H-4, J_(H3-H4) =8.00 Hz)7.93 (s, 1H, H-11) 7.82 (dd, 1H, H-2, J_(H1-H2) or J_(H2-H3) =6.67 Hz)7.65 (dd, 1H, H-3, J_(H2-H3) or J_(H3-H4) =8.00 Hz) 7.30 (dd, 1H, H-9,J_(H8-H9) =6.93 Hz, J_(H9-H11) =2.13 Hz)

IR (KBr): ν (cm⁻¹) 1699, 1650 (C═O), 1626 (C═N)

EXAMPLE 13

4-Chloro-5,6-dihydro-5,6-dioxo-naptho(1',2':4,5]imidazo[1,2-a] pyridine

A catalytic quantity of palladium on 10% carbon is added to an orangesuspension of 80 mg (0.27 mmol, 1 eq) of5,6-dihydro-5,6-dioxo-4-nitro-naphtho[1',2':4,5]imidazo-[1,2-a]pyridinein ethanol under argon, and the mixture is brought to reflux. 26.4 μL ofhydrazine monohydrate (0.27 mmol, 1 eq) are then added. The reactionmixture immediately becomes violet. After 30 min, 26.4 μL of hydrazinemonohydrate (0.27 mmol, 1 eq) are added. After 1 h of reaction, thereaction mixture is allowed to return to ambient temperature and thebrown-violet precipitate is filtered through dried cotton andsolubilized in 5 mL of conc. hydrochloric acid. This solution is cooledto -10° C., then a solution consisting of 34 mg (0.49 mmol, 1.8 eq) ofsodium nitrite and 5 mL of distilled water is added dropwise. The mediumis left under agitation at this temperature for 0.5 h. The reactionmedium is added dropwise to a solution cooled to -5° C., consisting of18 mg (0.18 mmol, 0.7 eq) of copper chloride(I) and 5 mL of conc.hydrochloric acid. The agitation is continued for 2.5 h. The reactionmixture is then diluted in dichloromethane, washed successively with asaturated solution of sodium carbonate, then with distilled water. Theorganic phase is extracted, then dried on sodium sulfate and evaporatedto dryness. The raw product is purified on preparation plates (support:silica, eluent: dichloromethane/methanol, 90/10) to produce 10 mg of4-chloro-5,6-dihydro-5,6-dioxo-naphtho[1',2':4,5]imidazo[1,2-a]pyridinein the form of yellow crystals.

Yield: 14%

Melting point: >260° C.

Rf: 0.60 (Dichloromethane/Methanol, 98/2)

MS (APcI-) : m/z 282/284 (M-)

¹ H-NMR (CD₂ Cl₂): δ (ppm) 9.14 (d, 1H, H-8, J_(H8-H9) =6.43 Hz) 8.16(d, 1H, H-1, J_(H1-H2) =7.54 Hz, J_(H1-H3) =1.51 Hz) 7.75 (d, 1H, H-11,J_(H10-H1) =8.41 Hz) 7.60 (t, 1H, H-10, J_(H9-H10) =J_(H10-H11) =8.40Hz) 7.53 (t, 1H, H-2, J_(H1-H2) =J_(H2-H3) =7.91 Hz) 7.46 (d, 1H, H-3,J_(H2-H3) =7.51 Hz, J_(H1-H3) =1.51 Hz) 7.15 (t, 1H, H-9, J_(H8-H9)=J_(H9-H10) =6.43 Hz)

IR (KBr): ν (cm⁻¹) 1662 (C═O)

EXAMPLE 14

4-Bromo-5,6-dihydro-5,6-dioxo-naphtho[1',2':4,5]imidazo[1,2-a] pyridine

A catalytic quantity of palladium on 10% carbon is added to an orangesuspension of 110 mg (0.37 mmol, 1 eq) of5,6-dihydro-5,6-dioxo-4-nitro-naphtho[1',2':4,5]imidazo[1,2-a]pyridinein ethanol under argon and the mixture is brought to reflux. 36.3 μL ofhydrazine monohydrate (0.37 mmol, 1 eq) are then added. The reactionmixture immediately becomes violet. After 30 min, 36.3 μL of hydrazinemonohydrate (0.37 mmol, 1 eq) are added. After 1 h of reaction, thereaction mixture is allowed to return to ambient temperature and thebrown-violet precipitate is filtered through dried cotton andsolubilized in 15 mL of conc. hydrobromic acid. This solution is cooledto -15° C., then a solution consisting of 64 mg (0.93 mm mmol, 2.5 eq)of sodium nitrite and 5 mL of distilled water is added dropwise. Themedium is left under agitation at this temperature for 1.5 h. Thereaction medium is added dropwise to a solution cooled to -5° C.,consisting of 21 mg (0.15 mmol, 0.4 eq) of copper(I) bromide and 5 mL ofconc. hydrobromic acid. A violet solution is obtained and its agitationis continued for 2.5 h. The reaction medium is then diluted indichloromethane, washed successively with a saturated solution of sodiumcarbonate, then with distilled water. The organic phase is extracted,dried on sodium sulfate and evaporated to dryness. The raw product ispurified on preparation plates (support silica, eluant:dichloromethane/methanol, 95/5) to produce 30 mg of4-bromo-5,6-dihydro-5,6-dioxo-naphtho[1',2':4,5]imidazo[1,2-a] pyridinein the form of yellow crystals.

Yield: 25%

Melting point: >260° C.

Rf: 0.60 (Dichloromethane/Methanol, 98/2)

MS (APcI+): m/z 326/328 (M⁺ H⁺)

¹ H-NMR(CD₂ Cl₂): δ (ppm) 9.13 (d, 1H, H-8, J_(H8-H9) =6.93 Hz) 8.21 (d,1H, H-1, J_(H1-H2) =7.42 Hz) 7.75 (d, 1H, H-11, J_(H10-H11) =8.90 Hz)7.71 (d, 1H, H-3, J_(H2-H3) =7.91 Hz) 7.60 (dd, 1H, H-10, J_(H9-H10)=J_(H10-H11) =8.90 Hz) 7.42 (t, 1H, H-2, J_(H1-H2) =J_(H2-H3) =7.42 Hz)7.15 (t, 1H, H-9, J_(H8-H9) =J_(H9-H10) 7.91 Hz)

IR (KBr): ν (cm⁻¹) 1610 (C═O)

EXAMPLE 15 OR EXAMPLE I

5,6-dihydro-5,6-dioxo-2-nitronaphtho[1',2':4,5]-imidazo[1,2-a] pyridineor

5,6-dihydro-5,6-dioxo-3-nitronaphtho[1',2':4,5]-imidazo[1,2-a] pyridine

0.42 g (4.41 mmol, 1.2 eq) of 2-aminopyridine is added to a solution of1.00 g (3.67 mol, 1.0 eq) of2,3-dichloro-1,4-dihydro-1,2-dioxo-6-nitronaphthalene in 200 mL ofethanol. The reaction mixture is brought to reflux for 24 h. Thereaction is allowed to cool to ambient temperature; the orangeprecipitate formed during the reaction is filtered and purified on aflash column (support: silica 6-35 μm, h=30 cm, δ=9 cm; conditioning:heptane/ethyl acetate, 70/30; eluant: heptane/ethyl acetate, 70/30, thendichloromethane/ethyl acetate, 50/50) to produce 0.20 g of5,6-dihydro-5,6-dioxo-2-nitronaphtho[1',2':4,5] imidazo[1,2-a]pyridineor 5,6-dihydro-5,6-dioxo-3-nitronaphtho[1',2':4,5]imidazo[1,2-a]pyridinein the form of ocher crystals after evaporation of the more polarfraction.

Yield: 18.5%

Melting point: >300° C.

Rf: 0.20 (heptane/ethyl acetate, 70/30)

MS (APcI-): m/z 293 (M-), 263 (M-NO)

¹ H-NMR (DMSO-d₆): δ (ppm) 9.36 (d, 1H, H-8, J_(H8-H9) =7.62 Hz) 8.96(s, 1H, H-1 of H-4, at α of the nitro) 8.57 (d, 1H, H-1 of H-4,J_(H1-H2) =J_(H3-H4) =8.54 Hz, at β of the nitro) 8.43 (d, 1H, H-2 ofH-3, J_(H1-H2) =J_(H3-H4) =8.54 Hz) 7.92 (d, 1H; H-11, J_(H10-H11) =7.63Hz) 7.75 (t, 1H, H-10, J_(H9-H10) =J_(H10-H11) =7.63 Hz) 7.32 (t, 1H,H-9, J_(H8-H9) =J_(H9-H10) =7.63 Hz)

IR (KBr): ν (cm⁻¹) 1649 (C═O), 1522 (NO₂)

EXAMPLE 16

6,11-dihydro-6,11-dioxo-7-nitronaphtho[2',3':4,5]imidazo [1,2-a]pyridine or

6,11-dihydro-6,11-dioxo-10-nitronaphtho[2',3':4,5]imidazo [1,2-a]pyridine

1.73 g (18 mmol, 1 eq) of 2-aminopyridine are added to a suspension of5.00 g (18 mmol), 1 eq) of2,3-dichloro-1,4-dihydro-1,4-dioxo-5-nitronaphthalene in 400 mL ofethanol. The mixture is brought to reflux for 5 h. After an orangeprecipitate appears, the reaction is allowed to cool to ambienttemperature and the precipitate is filtered and purified on a flashcolumn (support: silica 6-35 μm, h=45 cm, δ=16 cm; conditioning:heptane/ethyl acetate, 50/50; eluant: heptane/ethyl acetate, 50/50 to70/30) to obtain 0.54 g of6,11-dihydro-6,11-dioxo-7-nitronaphtho[2',3':4,5]imidazo[1,2-a]pyridineor6,11-dihydro-6,11-dioxo-10-nitronaphtho[2',3':4,5]imidazo[1,2-a]pyridine,which after recrystallization in 1,2-dichlorobenzene produces 0.24 g ofthe expected product in the form of orange crystals.

Yield: 4.5%

Melting point: >300° C. (decomposition)

Rf: 0.40 (heptane/ethyl acetate, 70/30)

MS (APcI+): m/z 294 (M+H⁺)

¹ H-NMR (CDCl₃): δ (ppm) 9.35 (d, 1H, H-1, J_(H1-H2) =6.38 Hz) 8.33 (d,1H, H-4, J_(H3-H4) =6.39 Hz) 7.89 (d, 1H, H-7 or H-10, J_(H7-H8) ofJ_(H9-H10) =8.44 Hz) 7.73-7.65 (m, 3H, H-2, H-3, H-8 or H-9) 7.27 (m,1H, H-8 or H-9, at β of the nitro)

IR (KBr): ν (cm⁻¹) 1660 (C═O) , 1540 (NO₂)

EXAMPLE 17

6,11-dihydro-6,11-dioxo-8-fluoronaphtho[2',3':4,5]imidazo [1,2-a]pyridine or

6,11-dihydro-6,11-dioxo-9-fluoronaphtho[2',3':4,5]-imidazo[1,2-a]pyridine or

5,6-dihydro-5,6-dioxo-2-fluoronaphtho[1',2':4,5]-imidazo [1,2-a]pyridineor

5,6-dihydro-5,6-dioxo-3-fluoronaphtho[1',2':4,5]-imidazo [1,2-a]pyridine

Intermediate product of synthesis:

2,3-dibromo-1,4-dihydro-1,4-dioxo-6-fluoronaphthalene

36 mL (710 mmol) of bromine are added to a solution of1,4-dihydro-1,4-dioxo-6-fluoronaphthalene (No. CAS 148541-61-1) (12.5 g,71 mmol) in chloroform (250 mL). The solution is brought to reflux for12 h, then brought to ambient temperature. After bubbling in compressedair, the solution is concentrated under reduced pressure and the solidobtained is washed five times with heptane. 15.0 g of a beige powder of2,3-dibromo-1,4-dihydro-1,4-dioxo-6-fluoronaphthalene are obtained.

Yield: 65%

Melting point: 158° C.

Rf: 0.80 (dichloromethane)

MS (APcI-): m/z 332, 334, 336 (M⁻)

¹ H-NMR (CDCl₃): δ (ppm) 8.22 (dd, 1H, H-8, J_(H7-H8) =8.55 Hz, J_(H-F)=5.19 Hz) 7.81 (dd, 1H, H-5, J_(H-F) =8.55 Hz, J_(H5-H7) =2.75 Hz) 7.45(td, 1H, H-7, J_(H-F) =J_(H7-H8) =8.55 Hz, J_(H5-H7) =2.75 Hz)

IR (KBr): ν (cm⁻¹) 1680 (C═O)

6,11-dihydro-6,11-dioxo-8-fluoronaphtho[2',3':4,5]-imidazo[1,2-a]pyridineor

6,11-dihydro-6,11-dioxo-9-fluoronaphtho[2',3':4,5]-imidazo[1,2-a]pyridineor

5,6-dihydro-5,6-dioxo-2-fluoronaphtho[1',2':4,5]-imidazo[1,2-a]pyridineor

5,6-dihydro-5,6-dioxo-3-fluoronaphtho[1',2':4,5]-imidazo [1,2-a]pyridine

1.4 g (15 mmol, 2 eq) of 2-aminopyridine are added to a suspension of2.5 g (7.5 mmol, 1.0 eq) of2,3-dibromo-1,4-dihydro-1,4-dioxo-6-fluoronaphthalene in 50 mL ofethanol. The reaction mixture is brought to reflux of the solvent for 20h, then brought to ambient temperature. The tan precipitate formed isfiltered and washed profusely with ethanol. The solid obtained ispurified by flash chromatography on a column of silica gel (support:silica 6-35 mm; (10 cm φ, 25 cm h; eluant: dichloromethane/ethylacetate, 70/30). 494 mg of6,11-dihydro-6,11-dioxo-8-fluoronaphtho[2',3':4,5]imidazo[1,2-a]pyridineor 6,11-dihydro-6,11-dioxo-9-fluoronaphtho[2',3':4,5]imidazo-[1,2-a]pyridine or 5,6-dihydro-5,6-dioxo-3-fluoronaphtho[1',2':4,5]imidazo[1,2-a]pyridine are obtained in the form of yellow crystals.

Yield: 42%

Melting point: >260° C.

Rf: 0.58 (dichloromethane/ethyl acetate, 70/30)

MS (APcI+): m/z 267 (M⁺ H⁺)

¹ H-NMR(CD₂ Cl₂): δ (ppm) 9.20 (d, 1H, H-pyridyl, J=6.72 Hz) 8.07 (dd,1H, H-aromatic, J=8.54 Hz, J_(H-F) =5.49 Hz) 7.81 (dd, 1H, H-aromatic,J_(H-F) =8.54 Hz, J=2.45 Hz) 7.78 (d, 1H, H-pyridyl, J=9.77 Hz) 7.63(td, 1H, H-aromatic, J_(H-F) =8.54 Hz, J=2.45 Hz) 7.16 (m, 2H,H-pyridyl)

IR (KBr): ν (cm⁻¹) 1660 (C═O)

EXAMPLE 18

6,11-Dihydro-6,11-7-fluoronaphtho[2',3':4,5]imidazo [1,2-a] pyridine or

6,11-Dihydro-6,11-dioxo-10-fluoronaphtho[2',3':4,5]-imidazo[1,2-a]pyridineor

5,6-Dihydro-5,6-dioxo-1-fluoronaphtho[1',2':4,5]-imidazo[1,2-a]pyridineor

5,6-Dihydro-5,6-dioxo-4-fluoronaphtho[1',2':4,5]-imidazo[1,2-a]pyridine

Intermediate synthesis product

2,3-Dibromo-1,4-dihydro-1,4-dioxo-5-fluoronaphthalene

7.34 mL (143 mmol) of bromine are added to a solution of1,4-dihydro-1,4-dioxo-5-fluoronaphthalene (No. CAS 62784-46-7) at 2.45 g71 mmol) in chloroform (60 mL). The solution is brought to reflux for 12h, then brought to ambient temperature. After bubbling with compressedair, the solution is concentrated under reduced pressure and the beigesolid product obtained is purified on a flash column (support: silica;conditioning: heptane; eluant: CH₂ Cl₂ /heptane) to produce 3.44 g of2,3-dibromo-1,4-dihydro-1,4-dioxo-5-fluoronaphthalene in the form ofbeige crystals.

Yield: 74%

Melting point: 100° C.

Rf: 0.63 (dichloromethane/heptane: 80/20)

MS (I.E.): m/z 333, 335, 337 (MH⁺•)

NMR of ¹ H (CDCl₃): δ (ppm) 8.01 (d, 1H, H-8, J_(H7-H8) =7.94 Hz) 7.77(m, 1H, H-7) 7.52 (m, 1H, H-6)

IR (KBr): ν (cm⁻¹) 1704 (C═O)

6,11-Dihydro-6,11-dioxo-7-fluoronaphtho[2',3':4,5]-imidazo[1,2-a]pyridineor

6,11-Dihydro-6,11-dioxo-10-fluoronaphtho[2',3':4,5]-imidazo[1,2-a]pyridineor

5,6-Dihydro-5,6-dioxo-1-fluoronaphtho[1',2':4,5]-imidazo[1,2-a]pyridineor

5,6-Dihydro-5,6-dioxo-4-fluoronaphtho[1',2':4,5]-imidazo[1,2-a]pyridine

0.885 g (9.4 mmol, 1 eq) of 2-aminopyridine is added to a suspension of3.77 g (11.28 mmol, 1.2 eq) of2,3-dibromo-1,4-dihydro-1,4-dioxo-5-fluoronaphthalene in 180 mL ofethanol.

The reaction mixture is brought to reflux, after 2 h it all passes intosolution. A tan precipitate appears after the fifth hour. After 15 h ofreflux, the ethanol is evaporated to dryness. A tan solid product isobtained and purified on a cake (support: silica 6-35 μm; conditioning:heptane; eluant: heptane/ethyl acetate: 90/10) to produce 375 mg of6,11-dihydro-6,11-dioxo-7-fluoronaphtho[2',3':4,5]imidazo[1,2-a]pyridine,6,11-dihydro-6,11-dioxo-10-fluoronaphtho[2',3':4,5]imidazo[1,2-a]pyridineor 5,6-dihydro-5,6-dioxo-4-fluoronaphtho[1',2':4,5]imidazo[1,2-a]pyridine in the form of yellow-orange crystals.

Yield: 15%

Melting point: >260° C.

Rf: 0.55 (AcOEt/Heptane, 70/30)

MS (I.E.): m/z 266 (M⁺.)

NMR of ¹ H (CD₂ Cl₂): δ (ppm) 9.27 (d, 1H, H-pyridyl, J=6.74 Hz) 7.89(dd, 1H, H-aromatic, J=7.02 Hz, J=1.22 Hz) 7.83 (d, 1H, H-pyridyl,J=9.13 Hz) 7.62 (m, 1H, H-pyridyl) 7.42 (m, 2H, H-aromatic) 7.19 (t, 1H,H-pyridyl, J=6.71 Hz)

IR (KBr): ν (cm⁻¹) 1700, 1645 (C═O)

EXAMPLE 19

4,9-Dichloro-5,6-dihydro-5,6-dioxonaphtho[1',2':4,5]imidazo[1,2-a]pyridine

125 mg (0.370 mmol, 1.0 eq) of9-chloro-5,6-dihydro-5,6-dioxo-4-nitronaphtho[1'2':4,5]imidazo[1,2-a]pyridineare heated to reflux in 150 mL of absolute ethanol under argon,palladium on carbon is then added, after 30 min, one hydrazineequivalent is added, then a second equivalent, and after 15 min a thirdequivalent, i.e., a total of 56 μL (1.11 mmol, 3.0 eq). The medium isfiltered cold.

The precipitate is solubilized in 20 mL of conc. hydrochloric acid. Thissolution is cooled to -17° C. and a solution consisting of 47 mg (0.67mmol, 2.0 eq) of sodium nitrite and 5 mL of distilled water is addeddropwise. The medium is agitated at this temperature for 0.5 h. Thereaction medium is added dropwise to a solution cooled to -10C,comprised of 67 mg (0.67 mmol, 2 eq) of copper(I) chloride and 5 mL ofconc. hydrochloric acid. The agitation is continued for 3 h. Thereaction medium is filtered. The organic phase is neutralized by solidsodium carbonate, then extracted in dichloromethane. The organic phaseis dried on sodium sulfate, filtered and evaporated to dryness. The rawproduct is purified on preparation plates (support: silica; eluant:dichloromethane/methanol, 98/2) to produce 8 mg of4,9-dichloro-5,6-dihydro-5,6-dioxonaphtho[1',2':4,5]imidazo[1,2-a]pyridinein the form of orange crystals.

Yield: 4%

Melting point: >260° C.

Rf: 0.27 (Dichloromethane/Methanol, 98/2)

MS (I.E.): m/z 316, 318, 320 (M⁺.)

NMR of ¹ H (CD₂ Cl₂): δ (ppm) 9.34 (d, 1H, H-8, J_(H8-H10) =1.74 Hz)8.20 (d, 1H, H-1, J_(H1-H2) =7.0 Hz) 7.76 (m, 1H, H-11) 7.79 to 7,56 (m,4H, H-10, H-2, H-3)

IR (KBr): ν (cm⁻¹) 1662 (C═O)

EXAMPLE 20

6,11-Dihydro-6,11-dioxo-7-methylnaphtho[2',3':4,5]-imidazo[1,2-a]pyridineor

6,11-Dihydro-6,11-dioxo-10-methylnaphtho[2',3':4,5]-imidazo[1,2-a]pyridineor

5,6-Dihydro-5,6-dioxo-1-methylnaphtho[1',2':4,5]-imidazo[1,2-a]pyridineor

5,6-Dihydro-5,6-dioxo-4-methylnaphtho[1',2':4,5]-imidazo[1,2-a]pyridine

Intermediate synthesis product:

2,3-Dibromo-1,4-dihydro-1,4-dioxo-5-methylnaphthalene

200 mL of carbon tetrachloride, then 17.2 mL (337 mmol, 4 eq) of bromineare added to 14.5 g (84 mmol, 1 eq) of1,4-dihydro-1,4-dioxo-5-methylnaphthalene. The solution becomes red,then 22.94 g (168 mmol, 2 eq) of sodium acetate are added. After 96 h ofreflux, the reaction medium is filtered, washed with carbontetrachloride and evaporated to dryness. The product is purified on acake (φ=6.5 cm, height=5 cm, deposit=solid, support=silica, eluant CH₂Cl₂). A tan-orange paste is obtained after evaporation to dryness. Afirst crystallization with dichloromethane produces 8.25 g of2,3-dibromo-1,4-dihydro-1,4-dioxo-5-methylnaphthalene in the form ofyellow crystals; a second recrystallization with acetonitrile produces11.90 g of 2,3-dibromo-1,4-dihydro-1,4-dioxo-5-methylnaphthalene in theform of yellow crystals.

Yield: 72%

Rf: 0.70 (ethyl acetate/heptane, 50/50)

MS (APcI-): m/z 328, 330, 332 (M⁻)

¹ H-NMR(CDCl₃): δ (ppm) 8.11 (dd, 1H, H-8, J_(H7-H8) =7.02 Hz, J_(H6-H8)=1.53 Hz) 7.63 (m, 2H, H-6, H-7) 2.76 (s, 3H, CH₃)

IR (KBr): ν (cm⁻¹) 1670 (C═O); 1570 (C═C)

6,11-dihydro-6,11-dioxo-7-methylnaphtho[2',3':4,5]-imidazo[1,2-a]pyridineor

6,11-dihydro-6,11-dioxo-10-methylnaphtho[2',3':4,5]-imidazo[1,2-a]pyridineor

5,6-dihydro-5,6-dioxo-1-methylnaphtho[1',2':4,5]-imidazo[1,2-a]pyridineor

5,6-dihydro-5,6-dioxo-4-methylnaphtho[1',2':4,5]-imidazo[1,2-a]pyridine

2.72 g (28.88 mmol, 2.4 eq) of 2-aminopyridine are added twice to asuspension of 4.00 g (12.12 mmol, 1 eq) of2,3-dibromo-1,4-dihydro-1,4-dioxo-5-methylnaphthalene in 500 mL ofethanol. This mixture is brought to reflux for 48 h. After cooling toambient temperature, the ethanol is eliminated by evaporation underreduced pressure. The2,3-dibromo-1,4-dihydro-1,4-dioxo-5-methylnaphthalene that did not reactis eliminated by precipitation in a CH₂ Cl₂ /heptane, 80/20 mixture. Theraw product is purified by chromatography on a preparation plate(support: silica SIL G-200 UV254 2 mm; eluant: CH₂ Cl₂ /EtOH, 97/3) toproduce 6,11-dihydro-6,11-dioxo-7-methylnaphtho[2',3':4,5]imidazo-[1,2-a]pyridine or6,11-dihydro-6,11-dioxo-10-methylnaphtho[2',3':4,5]imidazo[1,2-a]pyridineor5,6-dihydro-5,6-dioxo-4-methylnaphtho[1',2':4,5]-imidazo[1,2-a]pyridinein the form of yellowish-orange crystals.

Yield: 7%

Melting point: 218° C. (decomp)

Rf: 0.61 (CH₂ Cl₂ /EtOH, 97/3)

MS(I.E.): m/z 262 (M⁺.)

¹ H-NMR (CD₂ Cl₂): δ (ppm) 9.38 (d, 1H, H-pyridyl, J=6.64 Hz) 8.00 (d,1H, H-pyridyl, J=6.64 Hz) 7.84 (d, 1H, H-aromatic, J=8.72 Hz) 7.67 (m,1H, H-pyridyl) 7.52 (d, 1H, H-aromatic, J=7.47 Hz) 7.39 (t, 1H,H-aromatic, J=7.47 Hz) 7.23 (t, 1H, H-pyridyl, J=6.64 Hz) 2.98 (s, 3H,CH₃)

¹³ C-NMR(CDCl₃): δ (ppm) 139.34 (1C, C-aromatic) 132.30 (1C, C-pyridyl)130.30 (1C, C-aromatic) 129.35 (1C, C-pyridyl) 129.25 (1C, C-aromatic)118.91 (1C, C-pyridyl) 117.22 (1C, C-pyridyl) 23.18 (1C, CH₃)

IR (KBr): ν (cm⁻¹) 2940; 1745 (C═O); 1700 (C═C); 1650 (C═N)

EXAMPLE 21

2-chloro-6,11-dihydro-6,11-dioxo-7-methylnaphtho-[2',3':4,5]imidazo[1,2-a]pyridineor

2-chloro-6,11-dihydro-6,11-dioxo-10-methylnaphtho-[2',3':4,5]imidazo[1,2-a]pyridineor

9-chloro-5,6-dihydro-5,6-dioxo-1-methylnaphtho-[1',2':4,5]imidazo[1,2-a]pyridineor

9-chloro-5,6-dihydro-5,6-dioxo-4-methylnaphtho-[1',2':4,5]imidazo[1,2-a]pyridine

3.74 g (28.88 mmol, 2.4 eq) of 2-amino-5-chloropyridine are added twiceto a suspension of 4.00 g (12.12 mmol, 1 eq) of2,3-dibromo-1,4-dihydro-1,4-dioxo-5-methylnaphthalene in 500 mL ofethanol. This mixture is brought to reflux for 48 h. After cooling toambient temperature, the ethanol is eliminated by evaporation underreduced pressure. The2,3-dibromo-1,4-dihydro-1,4-dioxo-5-methylnaphthalene that had notreacted is eliminated by precipitation in a CH₂ Cl₂ /heptane, 80/20mixture. The raw product is purified by chromatography on a column(support: silica 6-35 mm, conditioning: CH₂ Cl₂ /heptane, 90/10, eluant:CH₂ /Cl₂ /AcOEt gradient, 100/0 to 50/50), then on a preparation plate(support: silica SIL G-200 UV 254 2 mm; eluant: CH₂ Cl₂) to produce2-chloro-6,11-dihydro-6,11-dioxo-7-methylnaphtho[2',3':4,5]imidazo[1,2-a]pyridin,2-chloro-6,11-dihydro-6,11-dioxo-10-methylnaphtho[2',3':4,5]imidazo[1,20-a]pyridine,9-chloro-5,6-dihydro-5,6-dioxo-1-methylnaphtho[1',2':4,5]imidazo[1,2-a]pyridine or 9-chloro-5,6-dihydro-5,6-dioxo-4-methylnaphtho[1',2':4,5]imidazo[1,2-a]pyridine in the form of orange crystals.

Yield: 6%

Rf: 0.76 (CH₂ Cl₂ /EtOH, 97/3)

MS(I.E.): m/z 296 et 298 (M⁺.)

¹ H-NMR(CD₂ Cl₂): δ (ppm) 9.33 (d, 1H, H-pyridyl, J=1.83 Hz) 7.91 (m,1H, H-aromatic) 7.69 (dd, 1H, H-pyridyl, J=0.91 Hz, J=9.46 Hz) 7.53 (dd,1H, H-pyridyl, J=2.14 Hz, J=9.46 Hz) 7.42 (m, 1H, H-aromatic) 7.31 (t,1H, H-aromatic, J=7.63 Hz) 2.86 (s, 3H, CH₃)

EXAMPLE 22

6,11-dihydro-6,11-dioxo-8-methylnaphtho[2',3':4,5]-imidazo[1,2-a]pyridineor

6,11-dihydro-6,11-dioxo-9-methylnaphtho[2',3':4,5]-imidazo[1,2-a]pyridineor

5,6-dihydro-5,6-dioxo-2-methylnaphtho[1',2':4,5]-imidazo[1,2-a]pyridineor

5,6-dihydro-5,6-dioxo-3-methylnaphtho[1',2':4,5]-imidazo[1,2-a]pyridine

2.72 g (28.88 mol, 2.4 eq) of 2-aminopyridine are added twice to asuspension of 4.00 g (12.12 mmol, 1 eq) of2,3-dibromo-1,4-dihydro-1,4-dioxo-6-methylnaphthalene (No. CAS72364-92-2) in 500 mL of ethanol. This mixture is brought to reflux for48 h. After cooling to ambient temperature, the ethanol is eliminated byevaporation, under reduced pressure. The2,3-dibromo-1,4-dihydro-1,4-dioxo-6-methylnaphthalene that had notreacted is eliminated by precipitation in a CH₂ Cl₂ /heptane, 70/30mixture. The raw product is purified by two successive chromatographieson a preparation plate (support: silica SIL G-200 UV254 2 mm; eluantfirst plate: CH₂ Cl₂ /MeOH, 97/3, and eluant second plate:heptane/AcOEt, 50/60) to produce6,11-dihydro-6,11-dioxo-8-methylnaphtho[2,,3':4,5]imidazo[1,2-a]pyridine,6,11-dihydro-6,11-dioxo-9-methylnaphtho[2',3':4,5]imidazo[1,2-a]pyridine, 5,6-dihydro-5,6-dioxo-2-methylnaphtho[1',2':4,5]imidazo[1,2-a]pyridine or 5,6-dihydro-5,6-dioxo-3-methylnaphth[1',2':4,5]imidazo[1,2-a]pyridine in the form of orange crystals.

Yield: 18%

Melting point: 244° C. (decomp.)

Rf: 0.67 (CH₂ Cl₂ /MeOH, 95/5)

MS(I.E.): m/z 262 (M⁺.)

¹ H-NMR(CD₂ Cl₂): δ (ppm) 9.36 (d, 1H, H-pyridyl, J=6.64 Hz) 8.12 (sl,1H, H-α of CH₃) 8.08 (d, 1H, H-β of CH₃, J=7.88 Hz) 7.91 (d, 1H,H-pyridyl, J=9.14 Hz) 7.75 (ddd, 1H, H-pyridyl, J=9.14 Hz, J=7.05 Hz,J=1.24 Hz) 7.44 (dd, 1H, H-α of CH₃, J=7.89 Hz, J=1.24 Hz) 7.32 (td, 1H,H-pyridyl, J=7.05 Hz, J=7.89 Hz) 2.60 (s, 3H, CH₃) ¹³ C-NMR(CDCl₃): δ(ppm) 132.34 (1C, C-aromatic) 131.66 (1C, C-aromatic) 130.27 (1C,C-pyridyl) 129.21 (1C, C-pyridyl) 125.53 (1C, C-aromatic) 118.45 (1C,C-pyridyl) 116.93 (1C, C-pyridyl) 22.06 (1C, CH₃)

IR (KBr): ν (cm⁻¹) 1700 (C═C); 1650 (C═N); 1600

EXAMPLE a

5,6-Dihydro-5,6-dioxo-naphtho[1',2':4,5]imidazo[1,2-a] pyridine

Reference: C.A. 58 12542e

Yield: 44%

Melting point: >260° C.

Rf: 0.50 (CH₂ Cl₂ /Methanol, 95/5)

MS (I.E.): m/z 248 (M+.)

¹ H-NMR (CDCl₃): (ppm) 9.07 (d, 1H, H-8, J_(H8-H9) =6.73 Hz) 8.06 (d,1H, H-1, J_(H1-H2) =7.53 Hz) 7.94 (d, 1H, H-4, J_(H3-H4) =7.99 Hz) 7.63(d, 1H, H-11, J_(H10-H11) =8.73 Hz) 7.51 (dt, 1H, H-2, J_(H1-H2)=J_(H2-H3) =7.43 Hz, J_(H2-H4) =1.02 Hz) 7.41 (dt, 1H, H-10, J_(H9-H10)=J_(H10-H11) =7.30 Hz, J_(H8-H10) =1.22 Hz) 7.33 (dt, 1H, H-3, J_(H2-H3)=J_(H3-H4) =7.95 Hz, J_(H1-H3) =1.03 Hz) 6.96 (dd, 1H, H-9, J_(H8-H9)=6.81 Hz

¹³ C-NMR(CDCl₃): (ppm) 181.5 (1C, C-5) 153.7 (1C, C-12a) 150.1 (1C,C-11a) 135.65 (1C, C-2) 132.50 (1C, C-10) 131.09 (1C, C-3) 130.44 (1C,C-4) 129.34 (1C, C-8) 124.94 (1C, C-1) 118.49 (1C, C-11) 5 116.50 (1C,C-9)

IR (KBr): ν (cm⁻¹) 1685, 1650 (C═O)

EXAMPLE b

5,6-Dihydro-5,6-dioxo-8-methylnaphtho[1',2':4,5]-imidazo[1,2-a]pyridine

Reference: C.A. 55 P25998e

Yield: 52%

Melting point: >260° C.

Rf: 0.55 (CH₂ Cl₂ /Methanol, 97/3)

MS (I.E.): m/z 262 (M+.)

¹ H-NMR(CDCl₃): (ppm) 8.21 (m, 2H, H-1, H-4) 7.72 (m, 3H, H-2, H-3,H-11) 7.51 (m, 1H, H-10) 6.97 (d, 1H, H-9, J_(H9-H10) =7.02 Hz) 3.12 (s,3H, CH₃) ¹³ C-NMR(CDCl₃): (ppm) 183.01 (1C, Cquat) 173.45 (1C, Cquat)151.45, 149.64 (2C, Cquat) 141.32 (1C, Cquat) 134.33, 133.06 (2C, C-2,C-3) 131.40, 126.71 (3C, C-1, C-4, Cquat) 127.36 (1C, C-10) 124.15 (1C,Cquat) 119.92 (1C, Cquat) 118.09 (1C, C-11) 117.24 (1C, C-9) 23.55 (1C,CH₃)

IR (KBr): ν (cm⁻¹) 1701, 1656 (C═O)

EXAMPLE c

9-Chloro-5,6-dihydro-5,6-dioxo-naphtho[1',2':4,5]-imidazo[1,2-a]pyridine

Reference: C.A. 55 P25998e

Yield: 61%

Melting point: >260° C.

Rf: 0.40 (CH₂ Cl₂ /Methanol, 98/2)

MS (I.E.): m/z 282 (M+.)

¹ H-NMR (CDCl₃): (ppm)

9.31 (dd, 1H, H-8, J_(H8-H10) =2.06 Hz, J_(H8-H11) =0.72 Hz) 8.14 (dd,1H, H-1, J_(H1-H2) =7.70 Hz, J_(H1-H3) =0.83 Hz) 8.11 (dd, 1H, H-4,J_(H3-H4) =7.79 Hz, J_(H2-H4) =1.04 Hz) 7.73 (dd, 1H, H-11, J_(H10-H11)=9.46 Hz, J_(H8-H11) =0.69 Hz) 7.68 (dt, 1H, H-2, J_(H1-H2) =J_(H2-H3)=7.57 Hz, J_(H2-H4) =1.31 Hz) 7.58 (dd, 1H, H-10, J_(H10-H11) =9.45 Hz,J_(H8-H10) =2.05 Hz) 7.51 (dt, 1H, H-3, J_(H2-H3) =J_(H3-H4) =7.66 Hz,J_(H1-H3) =1.20 Hz)

¹³ C-NMR(CDCl₃): (ppm) 181.45 (1C, C-5) 167.70 (1C, C-6a) 154.27 (1C,C-12a) 148.61 (1C, C-11a) 135.46 (1C, C-2) 133.13 (1C, C-10) 131.17 (1C,C-12b) 130.97 (1C, C-3) 130.79 (1C, C-4a) 130.31 (1C, C-4) 126.89 (1C,C-8) 124.95 (1C, C-9) 124.75 (1C, C-1) 118.34 (1C, C-11)

IR (KBr): ν (cm⁻¹) 1680, 1650 (C═O)

EXAMPLE d

9-Bromo-5,6-dihydro-5,6-dioxo-naphtho[1',2':4,5]-imidazo[1,2-a]pyridine

Reference: C.A. 55 P25998e

Yield: 21%

Melting point: 280° C.

Rf: 0.48 (CH₂ Cl₂ /Ethyl Acetate, 90/10)

MS (I.E.): m/z 326, 328 (M+.)

¹ H-NMR(270 Mhz, CDCl₃): δ (ppm) 9.45 (s, 1H, H-8) 8.17 (t, 2H, H-1,H-4, J_(H1-H2) =J_(H3-H4) =7.63 Hz) 7.71 (m, 3H, H-2, H-10, H-11) 7.54(t, 1H, H-3, J_(H2-H3) =J_(H8-H4) =6.94 Hz)

¹³ C-NMR(270 MHz, CDCl₃): δ (ppm) 135.5, 135.4 (2C, C-2, C-10) 131.0(1C, C-3) 130.4 (1C, C-4) 129.0 (1C, C-8) 124.8 (1C, C-1) 118.6 (1C,C-11) 111.4 (1C, C-9)

IR (KBr): μ (cm⁻¹) 1650, 1622 (C═O)

EXAMPLE e

5,6-Dihydro-5,6-dioxo-4-nitro-naphtho[1',2':4,5]-imidazo[1,2-a]pyridine

Reference: C.A. 55 P25998h

Yield: 25%

Melting point: >260° C.

Rf: 0.34 (CH₂ Cl₂ /Methanol, 98/2)

MS (I.E.): m/z 293 (M+.)

¹ H-NMR (CDCl₃): δ (ppm) 9.28 (d, 1H, H-8, J_(H9--H9) =6.41 Hz) 8.41 (d,1H, H-1, J_(H1-H2) =7.93 Hz) 7.85 (m, 2H, H-11) 7.72 (t, 1H, H-10,J_(H9-H10) =J_(H10-H11) =7.63 Hz) 7.50 (d, 1H, H-3, J_(H3-H4) =7.94 Hz)7.27 (t, 1H, H-9, J_(H8-H9) =J_(H9-H10) =6.10 Hz)

13C-NMR(CDCl₃): δ (ppm) 187.68, 182.16 (2C, C-5, C-6) 177.00 (1C, Cquat)144.90 (1C, C-4) 136.06 (1C, C-2) 132.86,(1C, C-10) 129.17 (1C, C-8)126.99 (1C, C-1) 124.54 (1C, C-3) 118.58 (1C, C-11) 117.40 (1C, C-9)

IR (KBr): μ (cm⁻¹) 1694, 1651 (C═O)

EXAMPLE f

5,6-Dihydro-5,6-dioxo-naphtho[1',2':4,5]-imidazo[1,2-a]pyridine

Reference: C.A. 55 P25998f

Yield: 37%

Melting point: >260° C.

Rf: 0.60 (CH₂ Cl₂ /Methanol, 98/2)

MS (I.E.): m/z 249 (M+.)

¹ H-NMR(CDCl₃): δ (ppm) 9.52 (d, 1H, H-8, J_(H9--H9) =5.00 Hz) 8.88 (d,1H, H-10, J_(H9-H10) =5.00 Hz) 8.20, 8.06 (2d, 2H, H-1, H-4, J_(H1-H2)=J_(H3-H4) =7.63 Hz) 7.78, 7.60 (2d, 2H, H-2, H-3) 7.45 (m, 1H, H-9)

13C-NMR(CDCl₃): δ (ppm) 169.33 (1C, Cquat) 155.58 (1C, Cquat) 136.24(1C, C10) 135.74, 131.46 (2C, C-1, C-3) 130.41, 125.70 (2C, C-1, C-4)125.53 (1C, Cquat) 112.41 (1C, C-9)

IR (KBr): μ (cm⁻¹) 1698, 1653 (C═O)

EXAMPLE g

6,11-Dihydro-6,11-dioxo-naphtho[2',3':4,5]-imidazo[1,2-a]pyridine

Reference: C.A. 55 21115b

Yield: 6%

Melting point: 293° C.

Rf: 0.10 (CH₂ Cl₂ /Ethyl Acetate, 96/4)

MS (I.E.): m/z 248 (M+.)

¹ H-NMR(CDCl₃): δ (ppm) 9.41 (d, 1H, H-1, J_(H1-H2) =6.72 Hz) 8.25 (m,2H, H-7, H-10) 7.92 (d, 1H, H-4, J_(H3-H4) =9.15 Hz) 7.79 (m, 2H, H-8,H-9) 7.66(m, 1H, H-2, J_(H1-H2) =J_(H2-H3) =7.02 Hz, J_(H2-H4) =1.22 Hz)7.28 (dt, 1H, H-3, J_(H2-H3) =J_(H3-H4) =7.02 Hz, J_(H1-H3) =0.91 Hz)

13C-NMR(CDCl₃): δ (ppm) 182.94 (1C, C=0) 176.30 (1C, C=0) 149.39, 146.19(2C, C-5a, C-11a) 134.47 (1C,C-8 ou C-9) 134.27, 134.11 (2C, C-6a,C-10a) 134.00 (1C, C-8 ou C-9) 131.23 (1C, C-3) 120.83 (1C, C-1) 127.55,126.82 (2C, C-7, C-10) 119.90 (1C, C-2) 117.46 (1C, C-4)

IR (KBr): μ (cm⁻¹) 1686, 1644 (C═O)

EXAMPLE h

6,11-Dihydro-6,11-dioxo-pyrido[1',2':1,2]-imidazo[5,4-g]quinoline

Reference: C.A. 116 151679t

Yield: 31%

Melting point: 260° C.

Rf: 0.51 (CH₂ Cl₂ /Ethanol, 94/6)

MS (I.E.): m/z 249 (M+.)

¹ H-NMR(CDCl₃): δ (ppm) 9.39 (d, 1H, H-1, J_(H1-H2) =7.02 Hz) 9.04 (d,1H, H-8, J_(H8-H9) =5.19 Hz) 8.60 (d, 1H, H-10, J_(H9-H10) =7.63 Hz)7.99 (d, 1H, H-4, J_(H3-H4) =9.16 Hz) 7.71 (m, 2H, H-2, H-9) 7.33 (m,1H, H-3)

13C-NMR(CDCl₃): δ (ppm) 154.19 (1C, C-8) 134.72 (1C, C-10) 131.73 (1C,C-3) 128.82 (1C, C-1) 127.86 (1C, C-9) 120.04 (1C, C-4) 117.82 (1C, C-2)

IR (KBr): μ (cm⁻¹) 1697, 1644 (C═O)

Pharmacological properties

The study of the compounds in the present invention and of their derivedsalts has demonstrated that they have various pharmacologicalproperties. Thus, they are selectively vasotonic, not affecting thearterial system except in concentrations much greater than those activeon the veins with the exception of certain arteries, the cerebralarteries in particular. The compounds show no, or at the most, very weakaffinity for the great majority of known receptors. Furthermore, theyincrease capillary resistance and diminish vascular hyperpermeabilityinduced by certain inflammatory agents.

These properties become evident in such mammals as hamsters, rats,guinea pigs, and rabbits, whether in vitro (isolated vessels or vascularnetworks) or in vivo.

For the in vitro studies, the compounds are made soluble in a pureaqueous solution or a solution containing DMSO (dimethyl sulfoxide).

As for the in vivo studies, they are administered intravenously orintraperitoneally in the form of an aqueous solution with or withoutDMSO, or orally in a 1% carboxymethylcellulose suspension, administeredwith the use of a force-feed probe at a volume of 10 mL/kg.

Pharmacological study models

Contractile effects

Contractile effects are measured, in vitro and under static conditions,on capacitance or resistance vascular rings of the saphenous, femoral,jugular, mesenteric, and caval veins; and on the femoral, carotid,basilar, mesenteric, and thoracic or abdominal aortic arteries, in rats(Wistar, 200 to 250 g), rabbits (New Zealand, 2 to 2.5 kg), and guineapigs (Dunkin Hartley, 250 to 300 g).

The rings are placed in an isolated organ chamber (25 mL for capacitancevessels and 2.5 mL for resistance vessels, as per Mulvany), kept inisometric conditions by two stiff cables inserted into the interior ofthe vessel, avoiding any damage to the endothelium. The vessels arewashed in a modified Krebbs solution (in mM: NaCl=118; KCl=4.6; ClCl₂=2.5; MgSO₄ =1.2; KH₂ PO₄ =1.17; NcHCO₃ =25; glucose=11), permanentlyaerated by a gaseous mixture at 95% O₂ and 5% CO₂, at pH=7.4 and setthermostatically at 37° C. The rings are taken to their optimal point ofthe tension-length ratio.

The tensions developed generate an electrical signal through a strengthsensor (Wheatstone bridge). This signal is amplified before either beingdisplayed on a Kipp & Zonen recorder or is digitalized for computeranalysis (IOS, EMKA). The pharmacological studies are carried out aftersome preliminary contractile stimulations standardized by a depolarizingsolution (hyperpotassic solution obtained by replacing NaCl by KCl inequimolar quantities), rinses, and balancing periods in purephysiological solution. Presence of the endothelium is verified by therelaxation induced by increasing concentrations of acetylcholine afterstabilization of a vascular precontraction.

The contraction forces developed by the vascular rings in response tothe different compounds are studied on quiescent or electricallystimulated (5-8 Hz) vessels, using a hyperpotassic depolarizingphysiological solution (KCl: 20, 40 mM), using noradrenaline (increasingconcentrations), or using serotonin (increasing concentrations).

The contractions are expressed in mg of force or as a percentage ofmaximum contraction at depolarization by a hyperpotassic physiologicalsolution.

The contractile effects are also measured in vitro in flux dynamicconditions, via the pressure developed by the vascular networks perfusedat a constant rate. At the mesenteric level, venoselectivity is studiedby the simultaneous and separate double perfusion model, developed by T.Warner (British Journal of Pharmacology, 1990, 99, 427-433). Separationof the two networks is obtained by cutting the vessels and tissues alongthe length of the intestinal border. The networks are perfused at 2mL·min⁻¹ by an aerated Krebbs solution (37.5° C.) at 95% O₂ and 5% CO₂.

In vivo, the arterial and venous pressures are measured in ananesthetized animal, under basal conditions and after circulatory arrestprovoked by inflating a balloon catheter inserted at the level of theright atrium. At the moment of cardiac arrest, the venous pressure(average circulation refill pressure at a constant blood volume) iscalculated from the venous and arterial pressures at equilibrium andcorrected as a function of the relative differences of compliancebetween the networks (Samar Coleman, American Journal of Physiology,234: H94-100, 1978; Yamamoto et al., American Journal of Physiology,238: H823-828, 1980).

In the case of the conscious animal, blood pressure is taken by theclassical method based on Riva Rocci, by analysis of the acoustical wavetransmitted at the arterial level and transformed by a ceramic piezotransducer placed on the rat's tail, below a sleeve automaticallyinflated by a pressure generator.

At the microcirculatory level, section variations in the venules andarterioles are studied in vivo by the method of placing a cutaneouschamber on the back of a conscious hamster, after videomicroscopy (LetzErgolux microscope equipped with a halogen source for lighting and anHPR 610 black-and-white CDD video camera) and computer analysis(Visicap, Pack JCAP software) of the images.

After anesthesia by sodium pentobarbital (60 mg/kg, i.p.), the animal'sback is shaved and depilated so that an observation chamber (Prof.Gebhard, Heidelberg) could be placed on the skin of the back. Both partsof the chamber are sown together after careful removal of a certainlevel of skin thickness that could impede observation. A jugularcatheter is placed for i.v. administration of the products 48 h afterthe operation.

Effects on induced capillary hyperpermeability

Vascular permeability is studied in vivo by measuring albuminextravasation, the quantity of which is determined by a coloring agentbonded to the albumin (Evans Blue). Hyperpermeability is induced by theintradermal injection of a histamine, bradykinin, or zymosan solution.

The technique is derived from that described by Beach and Steinetz,Journal of Pharmacology and Experimental Therapy, 131: 400-406, 1961.

The rats (Wistars, 200 to 230 g) are shaved on the abdominal wall 1 hbefore the start of the experiment. The product to be tested is injectedi.p. or orally 1-4 h prior to sacrificing. The rats are anesthetizedusing a halothane mixture. They then receive an intradermal injection inthe abdomen of 0.10 to 0.15 mL of an inflammatory agent (by histamine6.7 or 10 μg) and an i.v. injection of 1 mL of Evans blue 0.5% solutionin the vein of the penis. These injections are carried out 30 min priorto sacrificing.

30 min after these two injections, the rats are sacrificed by cervicaldislocation.

At the locus of injection of the inflammatory agent, the skin is cut offand placed in ground-neck glass tubes containing 3 mL of fuminghydrochloric acid. Digestion of the skin is carried out by contact [withHCl] of at least 1 h in a double boiler at 37° C.; 3 mL of benzalkoniumchloride at 12.8% are then added. After leaving undisturbed for 30 min,7 mL of dichloromethane are added. The tubes are periodically agitatedfor 1 h. The aqueous phase is eliminated by aspiration and the organicdichloromethane phase is filtered. The optical densities are quantifiedby absorption spectrophotometry at a 620 nm wavelength, against a blank[control] containing only dichloromethane.

The averages for optical density of the different lots of experimentaland control animals are calculated, then the variation between the datafor the experimental animals and those for the control animals iscalculated.

The effect of the compounds on the induced hyperpermeability byinflammatory agents, such as histamine and bradykinin, is likewisestudied after i.v. injection by bolus in the hamster dorsal cutaneouschamber model and according to the method developed by Gimeno et al.,previously described (A new technique using intravital videomicroscoyfor macromolecular permeability measurement, 18th EuropeanMicrocirculation Congress, Rome, 1994) by videomicroscopy and imageanalysis by quantification of intra- and extravascular fluorescencedistribution of the fluorescent marker (FITC-Dextran), injected by bolusby a jugular catheter (63 mg/kg for a volume defined at 1 mL/kg). Themicroscope is equipped with a fluorescene source and a combination cffilters (450-490-nm blue excitation and 515-nm stop filter).

Effects on capillary resistance:

The increase in capillary resistance is detected by the change in thepetechial index (negative pressure inducing the extravasation oferythrocytes), measured by a method derived from Parrot'sangiosterrometer.

The study is carried out on male Wistar rats weighing an average of 200g (aged approximately 6 weeks). The lower back area is shaved, thendepilated with the use of a paste based on a by-product of thioglycolicacid and calcium hydroxide. After approximately 30 min, the skin isrinsed abundantly and dried.

On the day of the study, the rats are kept nonconstrained. A lowpressure of 80 mm of mercury is applied. If the petechiae (erythrocyteextravasation) do not appear withing 15 sec, the low pressure isincreased by compensation, keeping the suction cup in the same place.

The minimum low pressure at which the petechiae appear expressed in mmof mercury, the value of the base capillary resistance (before anytreatment). Two measurements are carried out for each trial on differentplaces on the back. The rats are treated orally. After a predeterminedamount of time (generally 2, 4, or 6 h) after the treatment, the test isrenewed on different areas of skin, until petechiae appear, yielding anew low pressure index. All measurements are carried out in the blindmode.

The variation between the means of the base capillary resistance andpost-treatment capillary resistance is calculated for the experimentalanimals, for each treatment time and compared to the control group(excipient only) or the reference group.

Effects on induced pleurisy in rats:

The antiinflamatory activity of the compounds is also studied bymeasuring edema and leucocyte migration inhibition after the inductionof pleurisy in rats by the injection of carrageenin into the pleuralcavity (Almeida et al., Journal of Pharmacology and ExperimentalTherapy, 214: 74, 1980).

The rats are treated orally with the compounds 2 h before the injectionof carrageenin, as well as 2 and 4 h after such injection. After apredetermined amount of time (6 h) following the induction of pleurisy,the rats are sacrificed, the pleural liquid is recovered by aspiration,and its volume is measured. The leucocytes are counted by a cellcounter.

The results are expressed as the number of leucocytes in the exudate foreach 100 g of weight of the animal, and compared to the control group.

Examples of pharmacological effects:

The compounds of the invention and their derived salts selectivelyincrease, in the majority of cases, the contraction of animal veinsproduced by noradrenaline, by electrical stimulation, or by adepolarizing hyperpotassic solution. By way of example, there is thecontractile effect of different compounds on the saphenous vein ofrabbits, precontracted by a depolarizing physiological solution with apotassium concentration equal to 40 mM; the maximum effect produced byeach compound is expressed as the percentage of maximum contractioninduced by the depolarizing hyperpotassic solutions and in ED₅₀ values:

    ______________________________________                                        Compound   Emax(% of maximum contr.)                                                                      ED.sub.50 (nM)                                    ______________________________________                                        Example a  32 ± 7        306                                               Example c         27 ± 4                  157                              Example f         56 ± 7                  450                              Example h         18 ± 3                  67                               Example 1         20 ± 4                  170                              Example 2         28 ± 4                  271                              Example 3         18 ± 4                  200                              Example 12       13 ± 3                   58                               ______________________________________                                    

By way of example, the oral administration of certain compounds of theinvention and their derived salts increases the capillary resistance inrats at doses generally between 0.01 and 5 mg/kg:

    ______________________________________                                                       Effect at 4 hours                                                                         Effect at 6 hours                                  Compound                   (in % of control)                                                               (in % of control)                                ______________________________________                                          Example 2                                                                           5     mg/kg    11        13                                           Example c                                                                             5     mg/kg       17                      10                          Example c                                                                             0.1   mg/kg     19                        29                          Example c                                                                             0.1   mg/kg      0                         17                         Example h                                                                             0.1   mg/kg     19                        13                          ______________________________________                                    

By way of illustration, the oral administration of certain compounds ofthe invention and their derived salts reduce inflammatoryhyperpermeability induced by zymosan in rats in doses generally between0.01 and 5 mg/kg:

    ______________________________________                                                       Effect at 2 hours                                                                         Effect at 4 hours                                  Compound                     (in % of control)                                ______________________________________                                        Example a                                                                             5     mg/kg    -1        -28                                          Example c                                                                             0.1   mg/kg      -14                  -11                             Example h                                                                             0.1   mg/kg      -23                  -5                              Example 2                                                                             0.1   mg/kg      -10                  -15                             Example 3                                                                             5     mg/kg        -13                -12                             ______________________________________                                    

Furthermore, the compounds of the invention and their derived salts havea very low toxicity. For example, after a single oral administration of1 g/kg in mice, no toxic effect was observable and no mortality wasobservable for the majority of compounds, especially for Example a,Example c, and Example 2.

Among the preferred compounds of the invention, Example c is especiallysingled out.

The foregoing demonstrates that the compounds of the invention and theirderived salts may be used in human and animal therapy. They arespecifically indicated in functional organic venous insufficiency and inhemorrhoidal pathologies due to their vascular and anti-inflamatorycomponents, as well as in typically inflammatory disorders and in statesof shock caused by a significant drop in blood pressure. In the lattercase, an improvement in venous return may maintain the heart rate and,as a consequence, maintain the blood pressure.

Functional venous insufficiency is characterized by dilation andhyperdistensibility of the superficial veins in the legs, edema, andimpatience [unconfirmed translation] paresthesia of the restless legtype. This type of pathology may evolve toward organic venousinsufficiency characterized by the development of varicose veins,valvular incontinence, or towards thrombophlebitis and trophic disordersleading to ulcerative lesions.

In this venous pathology, an inflammatory component is established inthe first stages and becomes more clearly detectable in the advancedstages.

Due to their effects on vasoconstrictors, anti-inflammatories,especially on vascular hyperpermeability, and their contractile effectson cerebral arteries, the compounds of the invention and their derivedsalts are also indicated for migraine.

The present invention then includes the use of the above-mentionedcompounds and their derived salts as active substances for thepreparation of medications and pharmaceutical compositions for human andveterinary use, having at least one of said compounds and saltsassociated with a physiologically acceptable support or diluent.

The form of these medications and pharmaceutical compositions willobviously depend on the desired manner of administration--oral,parenteral, topical (cutaneous), and rectal--and they may be formulatedaccording to classical techniques, making use of the usual supports andvehicles.

Thus, in the case of oral administration, they may take the form ofpills, tablets, gels, solutions, syrups, emulsions, suspensions,powders, granules, soft capsules, lyophilizates, microcapsules, or microgranules.

Pills, tablets, and gels contain the active ingredient together with adiluent (for example, lactose, dextrose, sucrose, mannitol, maltitol,xylitol, sorbitol, or cellulose), a lubricant (for example silica, talc,or stearate), a bonding agent (for example, starch, methylcellulose orgum arabic), and/or a disintegration agent (alginate, for example); theyare manufactured by known methods, for example, mixing, granulation,lozenge-formation, coating, compression, etc.

Syrups may contain, as a support, glycerol, mannitol, and/or sorbitol.Solutions and suspensions may contain water and other physiologicallycompatible solvents and a support such as a natural gum, agar--agar,sodium alginate, or polyvinyl alcohol.

For parenteral administration, the medications and compositions may takethe form of solutions, emulsions, or suspensions containing the activeingredient and an appropriate support or solvent such as sterile wateror sterile isotonic solutions.

For cutaneous application, the medications and compositions may take theform of an ointment, creme, or gel, in the form of an emulsion orsuspension, solution, mousse, or powder.

For rectal application, the medications and compositions may take theform of a capsule, creme, emulsion, gel, mousse, paste, or suppository.

We claim:
 1. A method of treatment for an illness linked to alterationin venous function or inflammatory edema which comprises administeringan effective amount of a tetracylic derivative or, a pharmaceuticallyacceptable salt thereof, having the general formula: ##STR4## in which,independently of the other: X is a carbon atom,T is a carbon atom, R₁ isan atom of hydrogen, an atom of halogen, or a C₁ to C₅ alkyl radical, R₂is a hydrogen atom, a halogen atom, a nitro radical, or a C₁ to C₅ alkylradical, n and m are equal to 0 or to 1, but not independently of theother, so that if n is equal to 1, then m is equal to 0 and if n isequal to 0, then m is equal to
 1. 2. The method of claim 1 wherein saidtreatment is for functional and organic venous insufficiency.
 3. Themethod of claim 1 wherein said treatment is for hemorrhoidalpathologies.
 4. The method of claim 1 wherein said treatment is formigraines.
 5. The method of claim 1 wherein said treatment is forosteoarticular, dermatological, and cardiovascular inflammations.
 6. Themethod of claim 1 wherein said treatment is for shock caused by asignificant drop in blood pressure.
 7. The method of claim 6, whereinsaid shock is septic shock.
 8. A composition of matter comprising5,6-dihydro-5,6-dioxo-9-methyl-naptho[1',2':4,5]imidizo[1,2-a]pyridine.9. A composition of matter comprising5,6-dihydro-5,6-dioxo-10-methyl-naptho[1',2':4,5]imidazo[1,2-a]pyridine.10. A composition of matter comprising5,6-dihydro-5,6-dioxo-11-methyl-naptho[1',2':4,5]imidazo[1,2-a]pyridine.11. A composition of matter comprising11-chloro-5,6-dihydro-5,6-dioxo-naptho[1',2':4,5]imidazo[1,2-a]pyridine.12. A composition of matter comprising5,6-dihydro-5,6-dioxo-9-fluoro-naptho[1',2':4,5]imidazo[1,2-a]pyridine.13. A composition of matter comprising9-chloro-5,6-dihydro-5,6-dioxo-4-nitro-naptho[1',2':4,5]imidazo[1,2-a]pyridine.14. A composition of matter comprising2-chloro-6,11-dihydro-6,11-dioxo-7-nitro-naptho[2',3':4,5]imidazo[1,2-a]pyridine.15. A composition of matter comprising2-chloro-6,11-dihydro-6,11-dioxo-10-nitro-naptho[2',3':4,5]imidazo[1,2-a]pyridine.16. A composition of matter comprising6,11-dihydro-6,11-dioxo-2-methyl-naptho[2',3':4,5]imidazo[1,2-a]pyridine.17. A composition of matter comprising2-chloro-6,11-dihydro-6,11-dioxo-naptho[2',3':4,5]imidazo[1,2-a]pyridine.18. A composition of matter comprising4-chloro-6,11-dihydro-6,11-dioxo-naptho[2',3':4,5]imidazo[1,2-a]pyridine.19. A composition of matter comprising6,11-dihydro-6,11-dioxo-2-fluoro-naptho[2',3':4,5]imidazo[1,2-a]pyridine.20. A composition of matter comprising10-chloro-5,6-dihydro-5,6-dioxo-naptho[1',2':4,5]imidazo[1,2-a]pyridine.21. A composition of matter comprising4-chloro-5,6-dihydro-5,6-dioxo-naptho[1',2':4,5]imidazo[1,2-a]pyridine.22. A composition of matter comprising4-bromo-5,6-dihydro-5,6-dioxo-naptho[1',2':4,5]imidazo[1,2-a]pyridine.23. A composition of matter comprising5,6-dihydro-5,6-dioxo-2-nitro-naptho[1',2':4,5]imidazo[1,2-a]pyridine.24. A composition of matter comprising6,11-dihydro-6,11-dioxo-7-nitro-naptho[2',3':4,5]imidazo[1,2-a]pyridine.25. A composition of matter comprising6,11-dihydro-6,11-dioxo-10-nitro-naptho[2',3':4,5]imidazo[1,2-a]pyridine.26. A composition of matter comprising6,11-dihydro-6,11-dioxo-8-fluoro-naptho[2',3':4,5]imidazo[1,2-a]pyridine.27. A composition of matter comprising6,11-dihydro-6,11-dioxo-9-fluoro-naptho[2',3':4,5]imidazo[1,2-a]pyridine.28. A composition of matter comprising5,6-dihydro-5,6-dioxo-2-fluoro-naptho[1',2':4,5]imidazo[1,2-a]pyridine.29. A composition of matter comprising5,6-dihydro-5,6-dioxo-3-fluoro-naptho[1',2':4,5]imidazo[1,2-a]pyridine.30. A composition of matter comprising6,11-dihydro-6,11-dioxo-7-fluoro-naptho[2',3':4,5]imidazo[1,2-a]pyridine.31. A composition of matter comprising6,11-dihydro-6,11-dioxo-10-fluoro-naptho[2',3':4,5]imidazo[1,2-a]pyridine.32. A composition of matter comprising5,6-dihydro-5,6-dioxo-1-fluoro-naptho[1',2':4,5]imidazo[1,2-a]pyridine.33. A composition of matter comprising5,6-dihydro-5,6-dioxo-4-fluoro-naptho[1',2':4,5]imidazo[1,2-a]pyridine.34. A composition of matter comprising4,9-dichloro-5,6-dihydro-5,6-dioxo-naptho[1',2':4,5]imidazo[1,2-a]pyridine35. A composition of matter comprising6,11-dihydro-6,11-dioxo-7-methyl-naptho[2',3':4,5]imidazo[1,2-a]pyridine.36. A composition of matter comprising6,11-dihydro-6,11-dioxo-10-methyl-naptho[2',3':4,5]imidazo[1,2-a]pyridine.37. A composition of matter comprising5,6-dihydro-5,6-dioxo-1-methyl-naptho[1',2':4,5]imidazo[1,2-a]pyridine.38. A composition of matter comprising5,6-dihydro-5,6-dioxo-4-methyl-naptho[1',2':4,5]imidazo[1,2-a]pyridine.39. A composition of matter comprising2-chloro-6,11-dihydro-6,11-dioxo-7-methyl-naptho[2',3':4,5]imidazo[1,2-a]pyridine.40. A composition of matter comprising2-chloro-6,11-dihydro-6,11-dioxo-10-methyl-naptho[2',3':4,5]imidazo[1,2-a]pyridine.41. A composition of matter comprising9-chloro-5,6-dihydro-5,6-dioxo-1-methyl-naptho[1',2':4,5]imidazo[1,2-a]pyridine.42. A composition of matter comprising9-chloro-5,6-dihydro-5,6-dioxo-4-methyl-naptho[1',2':4,5]imidazo[1,2-a]pyridine.43. A composition of matter comprising6,11-dihydro-6,11-dioxo-8-methyl-naptho[2',3':4,5]imidazo[1,2-a]pyridine.44. A composition of matter comprising6,11-dihydro-6,11-dioxo-9-methyl-naptho[2',3':4,5]imidazo[1,2-a]pyridine.45. A composition of matter comprising5,6-dihydro-5,6-dioxo-2-methyl-naptho[1',2':4,5]imidazo[1,2-a]pyridine.46. A composition of matter comprising5,6-dihydro-5,6-dioxo-3-methyl-naptho[1',2':4,5]imidazo[1,2-a]pyridine.47. A composition of matter comprising2,3-dibromo-1,4-dihydro-1,4-dioxo-5-fluoronapthalene.
 48. A compositionof matter comprising2,3-dibromo-1,4-dihydro-1,4-dioxo-6-fluoronapthalene.
 49. A compositionof matter comprising2,3-dibromo-1,4-dihydro-1,4-dioxo-5-methylnapthalene.